The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. Hereditary Breast/Ovarian Cancer (HBOC) The first major clinical research project undertaken by CGB represents the next stage in DCEG's long-standing commitment to the study of hereditary breast and ovarian cancer (HBOC). The first priority with regard to these families is to make clinical predictive genetic testing for BRCA1/2 mutations available to interested family members (Protocol 02-C-0212). All families have been notified of their mutation status, and the process of bringing interested family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure is now underway. During the past year, 70 family members have undergone genetic risk assessment, and the majority of those have chosen genetic testing. Concurrently, we have mounted a new research protocol for these same individuals. This project is addressing issues related to breast cancer screening, early diagnosis, behavioral, educational and psychosocial dynamics related to the process of genetic risk assessment and testing. Under consideration, but not yet implemented, are studies of endogenous hormones as contributors to the risk of hereditary breast cancer, and decision-making by family members related to the use of tamoxifen as a breast cancer chemoprevention strategy. The first component of this study to begin patient accrual is a pilot study assessing mammography, MRI and PET imaging as screening tools for women at increased genetic risk of breast cancer (Protocol 02-2-0009). This protocol is actively accruing patients. This project will also assess the impact of menstrual cycle timing on breast MRI imaging characteristics (Protocol 02-C-0008), and provide us with an opportunity to evaluate breast duct lavage, a new technique for obtaining breast duct epithelial cells, as an early diagnosis tool in this setting, and as a potential source of biological materials for molecular genetic studies. The hereditary breast/ovarian cancer (HBOC) project has also provided the opportunity to initiate development of a behavioral/psychosocial research program within CGB. This activity will target individuals at increased genetic risk of cancer, and will draw upon the expertise of recently-recruited staff, including a genetic counselor, a psychiatric social worker and a cancer genetics research nurse. This project is being developed with the support of senior behavioral investigators from NCI's Division of Cancer Control and Population Studies, several of whom have joined CGB as Adjunct Investigators over the past year. Initial assessment is focusing on the experience of subjects participating in the Breast Imaging Study. Additional behavioral studies underway within the HBOC cohort include: (a) a pilot study of a novel tool (the Colored EcoGenetic Relations Map) for documenting individual and family support networks as a guide to genetic counseling; (b) a survey of the interest of male BRCA mutation carriers in participating in a prostate cancer intervention study; and (c) an assessment of mutation-negative women who persist in following screening programs designed for high-risk women. A study of the prevalence of BRCA1/2 founder mutations in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995 has documented a two-fold excess of prostate cancer among mutation carriers. This provides additional evidence in support of the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers. No major differences in age at diagnosis or in histopathology between mutation-related and mutation-unrelated have been identified. These findings have provided a more solid rationale for developing a study of prostate cancer screening and prevention among the men from our HBOC families who are mutation carriers. A survey of potential subject interest in such a project is underway to determine if it will be feasible. Inherited Bone Marrow Failure Syndromes (IBMFS) Study Our multidisciplinary research program targeting the inherited pediatric disorders which predispose to bone marrow failure, acute leukemia and, in adult survivors, solid tumors has now opened to patient accrual (Protocol 02-C-0052). Fanconi's Anemia is the prototype of these diseases, which also include dyskeratosis congenita, Diamond-Blackfan syndrome and Schwachman-Diamond syndrome. These rare disorders are being used as models for studying mechanisms of carcinogenesis in humans. Analysis of survey data collected by Dr. Blanche Alter, this study's PI, has documented dramatic increases in cancer risk among FA patients, with O/E ratios of 50, 785, 4317, 2362 and 706 for all cancers, leukemia, vulvar cancer, esophageal and head/neck cancers respectively. In particular, we will analyze the possible role of HPV in the etiology of the oral cavity and female genital malignancies which occur excessively in this setting. Genotype/phenotype correlations will be performed. An effort will be made to determine if persons who are heterozygous (carriers) for deleterious mutations in the FA genes are at increased risk of cancer. A series of psychosocial and behavioral sub-studies have been built into the IBMFS project. These include: (a) an assessment of baseline genetic knowledge among study participants; (b) an evaluation of coping mechanisms among family members; and (c) a study of survivor guilt among unaffected siblings. Familial Testicular Cancer Over the past year, we have re-activated DCEG's interest in familial testicular cancer. We are actively collaborating with the International Testicular Cancer Linkage Consortium in a series of studies related to this rare familial cancer syndrome. CGB investigators have taken the lead in designing a central review of the testicular cancer pathology and a quantitative analysis of the occurrence of cancers other than germ cell tumors in the Consortium family set. Data collection related to these two projects should begin in late 2002. In addition, we our new protocol for new testicular cancer families has opened to patient accrual (Protocol 02-C-0178). These families will contribute DNA for positional cloning of the X-linked testicular cancer susceptibility gene TGCT1, and to permit genome scanning for presumed additional autosomal susceptibility genes as well. Interested families will be broght to the NIH Clinical Center for a more detailed, etiologically oriented, clinical/genetic/laboratory study of the type that has historically been done so well by DCEG investigators. A manuscript is being prepared to bring to the attention of the US scientific community the entity of "testicular intraepithelial neoplasia," a critical testicular cancer precursor lesion which has received little consideration in the United States. In addition,the Familial Testicular Cancer Study has added assessments of: (a) baseline genetic knowledge among study participants; (b) general cancer screening practices among members of high-risk families; (c) participant adherence to risk-reducing and surveillance recommendations, as part of our expanding program of behavioral and psychosocial research; (d) interest in genetic testing; (e) attitudes about study participation; (f) beliefs and attitudes about cancer prevention, control and cure; (g) health locus of control; (h) family planning and reproductive choices; (i) health insurance experiences; (j) complementary and alternative medicine practices; (k) emotional health, distress, intrusive thoughts; and (l) personal support from family and others. Other Familial Cancer Syndromes The combination of breast cancer and colon cancer in different members of the same family seems to occur more often than can be accounted for by the known hereditary cancer syndromes. We are completing a literature review related to this association, which will serve as a basis for planning a family/genetic study of women with double primary cancers of the breast and colon in an effort to clarify this association. Evidence for an as yet unidentified cancer susceptibility gene will be sought. A study of familial cancer of the urinary bladder is now being developed. CGB also plays a role, as needed, in the analysis of family history data collected as part of ongoing analytic epidemiology studies conducted by colleagues elsewhere within DCEG. The first such project entails an assessment of family history of cancer and level of Westernization as cancer risk factors in a population-based, case-control study of breast cancer in Asian American women. Preliminary results suggest a possible synergism between environmental risk factors and genetic risk factors in the etiology of breast cancer among women of Asian ancestry who migrate to the United States. A manuscript is being prepared which describes the results of the baseline (T-zero) ovarian cancer screen in the PLCO cohort, stratified by familial risk of cancer. Our genetic counselor is co-author of a recent publication reviewing various mathematical models which are used for breast cancer risk assessment. Our Scientist Emeritus was the co-editor of a book on Werner's Syndrome. A report was published describing the contribution of the MET oncogene to the etiology of a series of sporadic cases of papillary renal cell carcinoma. Training CGB is also devoting significant attention and staff energy to the training of various health care professionals and researchers with an interest in clinical cancer genetics. Our first pre-doctoral candidate just successfully defended her PhD thesis in epidemiology. She analyzed the relationship between family history of breast cancer and the risk of developing either endometrial or ovarian cancer among women participating in DCEG's follow-up of the BCDDP cohort. The endometrial cancer manuscript is now in press; this analysis yielded a null result. The ovarian cancer analysis demonstrates that family history of breast cancer does increase the ovarian cancer risk, and does so in a pattern consistent with the action of the BRCA1/2 cancer susceptibility genes. \ The Clinical Genetics Branch has been approved by the American Board of Genetic Counseling as a Certified Training Site for genetic counseling graduate students from the NHGRI/Hopkins, Howard University and University of Maryland training programs. CGB's genetic counselor lectures annually at these same programs. We now have two post-doctoral cancer genetics fellows working with us, one a PhD in medical genetics and the other an MD, board-certified in medical oncology. Our staff also includes a DCP Prevention Fellow, who is a behavioral research investigator, and a nursing PhD candidate who will be doing her dissertation as part of the IBMFS project. As a certified training site for genetic counselor graduate students who are enrolled in the joint NHGRI/Johns Hopkins University School of Public Health masters' program, we have had a series of genetic counseling students rotate through our program during the last year.